RP1 gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: Retinitis pigmentosa 1
  • Regulates rhodopsin transport between the photoreceptor inner and outer segments through the connecting cilium
  • Maintaining the length and stability of the connecting cilium axoneme
  • Ensures correct stacking of the photoreceptor outer segment discs
Clinical phenotype
(OMIM phenotype no.)
  • Autosomal dominant (common)
  • Autosomal recessive
Signs for AD-RP
  • Vessel attenuation
  • Mid-peripheral bone spicule pigmentation
  • Profound peripheral RPE atrophy and foveal-sparing macular atrophy in later stages
  • Cystoid macular oedema
  • Optic disc pallor
  • Moderate myopia (-3.00 to -6.00D)
  • Posterior sub-capsular cataract
Signs for AR-RP
  • Typical RP features with profound peripheral RPE atrophy
  • Macular atrophy early in the disease process
  • Cystoid macular oedema
  • Early-onset cataract
  • Myopia
Visual functionAutosomal dominant RP1-retinopathy:
  • Onset of nyctalopia and/or peripheral VF loss around 2nd-4th decade of life
  • Relatively preserved BCVA even in advanced disease (6/24 or better)
  • Progressive VF loss and decline in 30 Hz cone ERG amplitudes, similar to AD-RP patients due to RHO mutations
  • Intra- and interfamilial variability in disease onset and severity due to variable expressivity and incomplete penetrance
Autosomal recessive/biallelic RP1-retinopathy:
  • Symptom onset usually in the 1st or 2nd decade in AR-RP cases
  • Progressive and rapid VA loss from adolescence/early adulthood to light perception in 6th decade of life
  • Severe and progressive VF constriction
  • Symptom onset later in AR-CORD and MD phenotypes; usually in the 4th decade (2nd-5th decade)
  • Mild to moderate VA impairment during working life to levels of 6/120 in the 8th decade
Systemic features
  • No extraocular features reported
Key investigations
  • Full field and pattern ERG
  • FAF in AD-RP: Central hyper-AF ring surrounded by speckled pattern of hypo- and hyper-AF, with patchy loss of AF in the periphery
  • OCT in AD-RP: Parafoveal loss of outer retinal layers while foveal lamination is relatively preserved even in advanced disease
  • FAF in biallelic cases: Central hyper-AF ring with early macular atrophy and variable degree of peripheral changes depending on clinical phenotype
  • OCT in biallelic cases: Outer retinal loss corresponding to macular atrophy; may be foveal-sparing in some patients
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Therapies under research
Further information

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Additional information

Mutations in RP1 cause 3-8% of AD-RP cases.[5-8] Most pathogenic RP1 mutations causing AD-RP are congregated between amino acid residues 500 and 1503 in exon 4 (a mutation hot-spot), where the p.Arg667X in the most common variant.[5,12]

On the other hand, biallelic variants can be situated in exons 2, 3 and 4 (outside of the AD-RP hot-spot). Exons 2 and 3 contain two doublecortin (DCX) domains which mediate the interaction between photoreceptor outer segment discs with axonemal microtubules.[12] A genotype-phenotype relationship can be observed in biallelic RP1 mutations[12]:

  • Presence of two truncating (result in the production of a shortened protein) or null alleles cause a severe and early-onset RP phenotype
  • Cone-rod dystrophy and MD are associated with the presence of at least one non-deleterious allele (truncating/null)
  • Missense variants in the exon 2 DCX region are associated with later-onset disease in all recessive phenotypes (RP, CORD and MD)

Furthermore, significant phenotypic variability is observed in biallelic RP1 variants. For example, patients from different families harbouring the same homozygous p.Asp202Glu variants can display either AR-RP, cone-rod dystrophy or MD phenotypes clinically.[13,14]

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Multimodal imaging

Multimodal imaging of a patient with heterozygous RP1 mutation. Wide field fundus photograph (A) shows bone-spicule hyperpigmentation and retinal atrophy in the mid-periphery, particularly in the nasal aspect. This is clearly visible on FAF imaging (B). There is a large hyperautofluorescent ring centrally as well. OCT scan through the macula (C) shows relatively well persevered retinal lamination and outer retinal layers.

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  1.  Gao J, Cheon K, Nusinowitz S, et al. Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene. Proc Natl Acad Sci U S A. 2002;99(8):5698-5703
  2.  Liu Q, Lyubarsky A, Skalet JH, Pugh EN, Jr., Pierce EA. RP1 is required for the correct stacking of outer segment discs. Invest Ophthalmol Vis Sci. 2003;44(10):4171-4183
  3.  Liu Q, Zhou J, Daiger SP, et al. Identification and subcellular localization of the RP1 protein in human and mouse photoreceptors. Invest Ophthalmol Vis Sci. 2002;43(1):22-32
  4.  Liu Q, Zuo J, Pierce EA. The retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein. J Neurosci. 2004;24(29):6427-6436
  5.  Bowne SJ, Daiger SP, Hims MM, et al. Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa. Hum Mol Genet. 1999;8(11):2121-2128
  6.  Pierce EA, Quinn T, Meehan T, McGee TL, Berson EL, Dryja TP. Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa. Nat Genet. 1999;22(3):248-254
  7.  Berson EL, Grimsby JL, Adams SM, et al. Clinical features and mutations in patients with dominant retinitis pigmentosa-1 (RP1). Invest Ophthalmol Vis Sci. 2001;42(10):2217-2224
  8.  Payne A, Vithana E, Khaliq S, et al. RP1 protein truncating mutations predominate at the RP1 adRP locus. Invest Ophthalmol Vis Sci. 2000;41(13):4069-4073
  9.  Jacobson SG, Cideciyan AV, Iannaccone A, et al. Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2000;41(7):1898-1908
  10.  Gamundi MJ, Hernan I, Martínez-Gimeno M, et al. Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population. BMC Med Genet. 2006;7:35
  11.  Audo I, Mohand-Saïd S, Dhaenens CM, et al. RP1 and autosomal dominant rod-cone dystrophy: novel mutations, a review of published variants, and genotype-phenotype correlation. Hum Mutat. 2012;33(1):73-80
  12.  Verbakel SK, van Huet RAC, den Hollander AI, et al. Macular Dystrophy and Cone-Rod Dystrophy Caused by Mutations in the RP1 Gene: Extending the RP1 Disease Spectrum. Invest Ophthalmol Vis Sci. 2019;60(4):1192-1203
  13.  Riera M, Abad-Morales V, Navarro R, et al. Expanding the retinal phenotype of RP1: from retinitis pigmentosa to a novel and singular macular dystrophy. Br J Ophthalmol. 2020;104(2):173-181
  14.  Huckfeldt RM, Grigorian F, Place E, et al. Biallelic RP1-associated retinal dystrophies: Expanding the mutational and clinical spectrum. Mol Vis. 2020;26:423-433. Published 2020 Jun 3

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Updated on November 30, 2020
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